Vaccines have been responsible for preventing millions of deaths and extending the average human lifespan. This remarkable record of success has not been unsullied and vaccine formulation, host genetic background, age, immune history and other factors influence immune responses to vaccination in ways that are underexplored. A better understanding of these factors and the correlates of vaccine success versus failure should provide a useful blueprint for improving current vaccines and developing new vaccines against prevalent and emerging pathogens. Essential in the innate immune control of viral infections, type I interferons (IFNs) are traditionally described as immunostimuiatory and antiviral cytokines. However, emerging evidence suggests a paradoxical role for type I IFN in suppressing certain innate and adaptive immune functions. Chronic Infection by hepatitis C virus (HCV) causes constitutive IFN stimulation, which may contribute to viral persistence in spite of immune defense mechanisms. Although not considered generally immunocompromised, chronic HCV patients demonstrate high failure rates to hepatitis B virus (HBV) vaccination. We hypothesize that this poor response is due to the immunomodulatory effects of persistent innate immune activation by chronic HCV infection. In collaboration with our clinical colleagues at Weill Cornell, our CCHI clinical core and complementing CCHI projects, we propose a comprehensive examination of HBV vaccine response in patients chronically infected with HCV. We will recruit chronic HCV patients and healthy controls for HBV vaccination, measure their innate immune status by Interferon-stimulated gene expression in peripheral blood, and determine its association to HBV vaccine response. We will then characterize those immune mechanisms compromised in chronic HCV by assessing the HBV-specific adaptive immune response, and the innate inflammatory response to vaccine antigen and adjuvant. These studies will enhance our understanding of the immunomodulatory effects of chronic viral Infection, establish determinants of effective vaccine responses, and help guide vaccination strategies for HCV patients and other individuals with chronic inflammatory disease.